6-halopenicillanic acid



United States Patent 3,206,469 6-HALOPENICILLANIC ACID Giorgio Piiieri, Milan, Italy, assignor to Lepetit S.p.A., Milan, Italy No Drawing. Filed July 9, 1962, Ser. No. 208,579 Claims priority, application Great Britain Aug. 15, 1961 3 Claims. (Cl. 260-3067) wherein X is a halogen atom.

The process for preparing the new compounds consists in diazotizing 6-aminopenicillanic acid at 02 C. in the appropriate diluted hydrohalogen acid; the e-lactam ring, although generally easily hydrolysed, is not affected in the above diazotization conditions and the compound can be isolated in good yields.

The halopenicillanic acids of the invention show a high degree of antibacterial activity, as shown in the following table, which gives the minimum inhibitory concentration in meg/ml. on some microorganisms:

fi-chloropenieilfi-bromopeuilanic acid eiilanic acid The halopenicillanic acids of the invention can also be useful as intermediates for the preparation of antimicrobiologically active substances having the penicillin ring system.

The following non-limitative examples illustrate the invention.

EXAMPLE 1 6-chl0r0penicillanic acid A solution of 6.5 g. of 6-APA in 100 ml. of N hydrochloric acid is cooled to 0-2 C. and a solution of 2.5 g. of sodium nitrite in 20 ml. of water is added dropwise. One hour after the completion of the addition, the temperature is allowed to rise to 1518 C. and the separated oil extracted with ethyl ether.

The organic layer is dried over sodium sulphate and the ether evaporated in vacuo at room temperature.

The oily residue, 4.5 g. shows in the infra red spectrum bands at 1725 cm. (C=O stretching of carboxylic group) and at 1770 emf (C=O stretching of fl-lactam fused to thiazolidine ring) in agreement with the expected structure.

This oil, which decompises under distillation, is dissolved in ethyl ether and treated with an ether solution of dibenzylethylenediamine: 5.5 g. of dibenzylethylenediamine salt are obtained, which, after several crystallisations from aqueous ethanol, melts at 159150 C.; [a] =-[-154.4- (c.=0.5% in methanol).

Analysis.Calcd. 01 C H Cl N O S C, H, 5.67; N, 7.88; S, 9.01; Cl, 9.97. Found: C, 53.75; H, 6.19; N, 7.65; S, 8.99; Cl, 10.24.

EXAMPLE 2 6-br0m0penicillanic acid It is prepared essentially in the same way described in Example 1, starting from 4.32 g. of 6APA dissloved in 50 ml. of 2.5 N sulphuric acid containing 10.4 g. of sodium bromide and adding dropwise a solution of 2.12 g. of sodium nitrate in 10 m1. of water. The oily residue (4.88 g.) shows infrared bands at 1770 and 1725 cmf On treatment with an ether solution of dibenzylethylenediamine, 3.4 g. of dibenzylethylenediamine salt are obtained, which, recrystallized from aqueous ethanol, melts at 164-165 C.; [oc] =+14O.9 (C:0.5% in methanol).

Analysis.Calcd. for C H Br N O S C, 48.00; H, 5.03; N, 6.99; S, 8.00; Br, 19.96. Found: C, 48.17; H, 5.11; N, 7.28; S, 7.85; Br, 19.90.

I claim:

1. A 6-halopenicillanic acid of the formula:

wherein X is a member of the class consisting of chlorine and bromine atoms.

2. 6-chloropenicillanic acid.

3. 6-bromopenicillanic acid.

References Cited by the Examiner UNITED STATES PATENTS 2,941,995 6/ Doyle et a1 260-2391 3,040,032 6/ 62 Doyle et al 260239.1 3,041,333 6/62 Chow et al 260-239.1 3,071,575 l/63 Doyle et al 260-2391 3,071,576 1/63 Doyle et a1 260239.1

OTHER REFERENCES Morton: The Chemistry of Heterocyclic Compounds, page VI of the preface (1946).

Simons: Fluorine Chemistry, page 402 (1950).

Wertheim: Textbook or Organic Chemistry, pages 79-81 and 310-311 (1945).

NICHOLAS S. RIZZO, Primary Examiner, 

1. A 6-HALOPENICILLANIC ACID OF THE FORMULA: 